Tetrahydronaphthylalkanoic acids and their derivatives

ABSTRACT

NOVEL TETRAHYDRONAPHTHYLALKANOIC ACIDS AND THEIR DERIVATIVES SUCH AS ALPHA, 4-DICHLORO-5,6,7,8-TETRAHYDRO-2NAPTHYLACETIC ACID AND ITS DIETHYLAMMONIUM SALT, USEFUL FOR THE TREATMENT OF INFLAMMATION AND ASSOCIATED PAIN AND FEVER, ARE DESCRIBED.

United States Patent Oflice Patented Aug. 13, 1974 3,829,467TETRAHYDRONAPHTHYLALKANOIC ACIDS AND THEIR DERIVATIVES Julius Diamond,Lafayette Hill, and George Henry Douglas, Paoli, Pa., assignors toWilliam H. Rorer, Inc., Fort Washington, Pa. No Drawing. Filed July 3,1972, Ser. No. 268,745 Int. Cl. C07c 63/50 US. Cl. 260501.16 2 ClaimsABSTRACT OF THE DISCLOSURE Novel tetrahydronaphthylalkanoic acids andtheir derivatives such as alpha, 4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid and its diethylammonium salt, useful for thetreatment of inflammation and associated pain and fever, are described.

CROSS REFERENCES TO RELATED APPLICATIONS None.

SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION Continued studieshave been carried out in research to develop drugs which wouldsignificantly inhibit the development of inflammation and relieve thepain and fever associated with it. Much of this effort has been carriedout in the steroid field; however, there have been compounds developedwhich are non-steroidal and have included such as the alkanoic acidsderived from the cycloalkylphenyl ring system.

We have unexpectedly found that when a hydroxy, halo, or thio group orderivative thereof is present in the u-position of the side chain of asubstituted tetrahydro-Z- naphthylacetic acid molecule, pharmacologicalproperties exist in the molecule which are useful for the relief andinhibition of inflammation conditions.

We have also found that the compounds of this invention are effective inthe treatment of inflammation and the control of arthritic conditionsassociated with inflammation.

We have further found that a-hydroxy, halo andthiotetrahydro-Z-naphthylacetic acids and their derivatives are novel.

We have also found that the compounds of this invention possess usefulanalgesic and antipyretic properties and are useful in the treatment ofpain and fever.

We have still further found an entirely new class of anti-inflammatory,analgesic and antipyretic pharmaceutical compositions which contain ane-hydroxy, halo or thiotetrahydro-Z-naphthylacetic acid or derivativethereof as active ingredient.

We have also found a convenient method for synthesizing these compounds.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention comprises a classof novel chemical compounds which are5,6,7,8-tetrahydro-Z-naphthylacetic acids or derivatives to which isattached a hydroxy, hydroxy derivative, halo, mercapto, or thioderivative at the a-position of the acetic acid side chain. Also thetetrahydronaphthyl ring may further be substituted.

This invention also describes a new method for treating inflammation aswell as pain and fever and also novel therapeutic compositions.

The compounds of this invention can be represented by the genericstructure which is described by the general formula I where R ishydrogen, alkyl, halo, amino, acylamino, mono and diloweralkylamino,mercapto, acylthio, hydroxy, loweralkoxy, aryloxy, acyloxy,haloloweralkyl, cyano, acctyl or benzoyl;

R, is hydrogen or loweralkyl;

X is hydroxy, acyloxy, loweralkanesulfonyloxy, arylsulfonyloxy, halo,mercapto, acylthio;

is hydrogen, -OH, loweralkoxy, arloweralkoxy,

NH loweralkylamino, diloweralkylamino, cycloloweralkylamino,

(where A is loweralkylidenyl or heteroloweralkylidenyl), NHOH, NHNH orOM (where M is an alkali, alkaline earth or aluminum metal or anammonium salt).

The preferred position for substitution is the 4-position.

The preferred compounds of this invention are described by formula Iwhere R is in the 4-position and R, is hydrogen.

The more preferred compounds are those where R is 4- halo or 4-nitro, R,is hydrogen and X is hydroxy or halo.

The most preferred compounds are those where R is 4- halo, R, ishydrogen, X is hydroxy or chloro and Z is OH, amino, diloweralkylaminoand OM.

The compounds of this invention contain an asymmetric carbon atom in theacid side chain. As a result, the above compounds of formula I may beobtained as racemic mixtures of their dextro and levorotatory isomers.It is to be understood that said (1 and l isomers as well as the dlmixtures thereof are embraced within the scope of this invention.

The compounds of this invention may be prepared from known startingmaterials. References to specific starting materials are given whereapplicable or the following methods of synthesis may be used whereappropriate.

Friedel-Crafts condensation of 5,6,7,8-tetrahydronaphthlene with analkyl (preferably t-butyl) or aralkyl oxalyl chloride in the presence ofanhydrous aluminum chloride results in5,6,7,8tetrahydro-ZnaphthylglYoxylate. This may then be reacted with analkyl Grignard reagent to form thea-alkyl-5,6,7,8-tetrahydro2-naphthylglycolate or 3 4 it may be reducedto the glycolate *by catalytic hydrogena- An amino compound may bemonoor dialkylated with tion with platinum oxide or under sodiumborohydride lower alkyl halides or sulfates or acylated with loweracylconditions. chlorides or anhydrides.

1? if I? CK JCOOR' U-OOOR" 5 C-GOOR" H C-COOR" A1013 1 111 I IHR" lRaMgX RCOC1 or H 0H (iJH (RC )z HAJOOR" (J-COOK" (l? R.z -CCOOR C-GOOR"Appropriately desired end products having various R H H substituents canbe prepared at various stages of the NHCOR MR )1 synthesis by usingsuitable reactions in order to convert An amino compound may bediazotized followed by a one group to another- Thus, for 'f theglyfmylate Sandmeyer type reaction to yield the halo group. may bealkylated, halogenated or nltrated to obtain sub- 0 0 stitution in the4-position. 1| 1| 0 COO0R" BN0 C--COOR" ll C-GOOR OuBr NH: Br NO: l AND:(I? E 3 C111 0-0003" 0-0003" 6 C-COOR O-GOOR" lal o I H Cl I C COOR Anamino compound may also be diazotized to the diazonium fluoroboratewhich is then thermally decom- 40 posed to the corresponding fiuorocompound.

Alk 0 II o-ooorw C-COOR" A mtro glyoxylate may 'be hydrogenated to thecorresponding amine. HBF4 o (i-000R" i-000R" NHZ NIB F4 i NH:

An amino compound may be diazotized and heated in an aqueous medium toform the hydroxy compound or heated in an alcohol to form the alkoxycompound. The hydroxyl group may also be alkylated with loweralkyl Lhalides or sulfates to the alkoxyl group or acylated with loweracylchlorides or anhydrides to the acyloxy compound in the presence of atertiaryamine such as pyridine.

It may also be diazotized and heated with an aqueous solution ofpotassium iodide to prepare the iodo compound.

II arc-COOK HZNO2 C 000R (|'|J COOR HNO g /I H10 KI 1 111 (in I l 1 35NH; I

\ pyridinel It may further be diazotized and followed by addition ofcuprous cyanide to obtain the cyano compound.

0 O H H C-COOR" C-COOR" NH: JN

An aminoglyoxylate may be diazotized followed by reaction with potassiumethylxanthate followed by hydrolysis to obtain the mercaptoglyoxylatewhich can be esterified to a mercapto glyoxylate. This, in turn, can belower alkylated to the lower alkylthio and oxidized to the loweralkylsulfinyl and lower alkylsulfonyl groups or acylated to the acylthiocompounds.

ll C-COOR (1) HNOz K s 0 s 002135 A halo compound in which halo ischloro or bromo or iodo may be reacted with cuprous cyanide in quinolineat about 150 C. to produce a cyano compound:

0 Cj ko 0 0R" CuCN @(Looo R" Ilia] N or reacted withtrifluoromethyliodide and copper powder at about 150 C. indimethylformamide to obtain a trifluoromethylglyoxylate or lactate [asdescribed in Terrahedron Letters: 47, 4095 (1959)]:

CF31 0-0 0 O R" A haloglyoxylate may also be reacted with cuprousmethanesulfinate in quinoline at about 150 C. to obtain amethylsulfonylglyoxylate.

Hal

The substituted glyoxylate may be selectively reduced to the glycolateor treated as above with a Grignard reagent to form an a-alkylglycolate.

Reaction of a 5,6,7,8-tetrahydro-2-naphthylglycolate ester with anitrogen base such as ammonia, loweralkylamine, diloweralkylamine,cycloloweralkylamine, a nitrogen containing hetero compound such aspiperidine, morpholine, piperazine, hydroxylamine and hydrazine givesthe corresponding amide, hydroxamic acid, or hydrazide.

The 5,6,7,8-tetrahydro-2-naphthylglycolate esters may be hydrolyzed tothe corresponding glycolic acids. Reaction of the glycolate ester orglycolic acid with an acyl chloride XCl or acyl anhydride X'OX in thepresence of a tertiary amine such as pyridine, picoline, or quinolineresults in the formation of an acyloxy compound. Examples of X'Cl andX'OX include acetyl chloride, acetic anhydride, propionyl chloride,butyryl chloride, succinic anhydride, maleic anhydride, phthalicanhydride, benzoyl chloride, benzoic anhydride, benzyl chlorocarbonate,ethyl chlorocarbonate, dimethylcarbamyl chloride, dibutylcarbamylchloride, benzenesulfonyl chloride, methanesulfonyl chloride.

OH OH iJ-ooorw alcKOH til-COOK b-ooon" CCOOH Rn t! When a substituted5,6,7,8-tetrahydro-Z-naphthylglycolate is reacted with a phosphorustrihalide, phosphorus pentahalide, phosphorus oxyhalide, sulfurylhalide,thionyl halide, or sulfur halide, the corresponding substituted5,6,7,8-tetrahydro-2-naphthyl-a-halo acetate is prepared.

OH Hal --+-COOR" i t-ooon" Rm R.

where R" is lower alkyl; and Hal is chloro, bromo or iodo.

Reaction of a 5,6,7,8-tetrahydro-2-naphthyl-a-sulfonate compound with ametal halide (preferably an alkali halide) also results in thecorresponding a-halo compound.

where Z is as described in column 2.

7 The corresponding 5,6,7,8 tetrahydro-2-naphthyl-ahaloacetic acid maybe prepared by heating the ester with acetic acid containing thecorresponding hydrogen halide.

Hal Hal -COOR HOAc 41-COOH HHal where R" is lower alkyl.

The substituted 5,6,7,8-tetrahydro-2-naphthyl-a-fiuoro compounds mayalso be obtained from the corresponding a-iodo, a-bromo or a-chlorocompounds by reaction with potassium fluoride at about l200 C.

R lKF 1.31 (ll-COOK" H The acid addition salts may be formed by theaction of one equivalent of a suitable base with the substituted 5,6,7,8-tetrahydro-2-naphthyl-a-haloacetic acid. Suitable bases thus includefor example the alkali metal alkoxides such as sodium methoxide, etc.,and the alkali metal and alkaline earth metal hydroxides, carbonates,bicarbonates, etc. (such as sodium hydroxide, potassium hydroxide,calcium hydroxide, potassium carbonate, sodium bicarbonate, magnesiumbicarbonate, etc.). Also, the aluminum salts of the instant products maybe obtained by treating the corresponding sodium salt with anappropriate aluminum complex such as aluminum hydroxy chloridehexahydrate, etc. The ammonium salts may be made by reaction with thecorresponding amine such as methylamine, diethylamine,B-hydroxyethylamine, piperazine, piperidine, ot-methylbenzylamine,cyclohexylamine, triethylamine, phenethylamine, etc.

Reaction of a substituted 5,6,7,S-tetrahydro-Z-naphthyla-halo acetatewith a nitrogen base such as ammonia, loweralkylamine,dilo'weralkylamine, cycloloweralkylamine, a nitrogen containing heterocompound such as piper-idine, morpholine, piperazine results in thecorresponding amide. The acetate with hydroxy amine gives thecorresponding hydroxarnic acid, and with hydrazine gives thecorresponding hydrazide.

Hal

where: Z is NH loweralkylamine, diloweralkylam'ino,cycloloweralkylamino,

A -N B (where B is loweralkylidenyl or heteroloweralkylidenyl), NHOH orNHNH The 5,6,7,8-tetrahydro-Z-naphthyl-a-halo acetamides,racethydr'oxamic acids, and acethydrazides, can be prepared from thecorresponding glycolamides with thionyl halides according to the methodof I. A. Smith, Chem. Berichte, 71Bz634 (1938).

The substituted 5,6,7,8-tetrahydro-2-n-aphthyl-or-halo acetic acids andacid derivatives such as their salts, amides or esters may be reactedwith various nucleophilic reagents which will replace the a-halogengroup. Thus for example, an alkali hydrosulfide or an alkalithioalkanoate may be reacted to obtain an a-mercapto or wacyl-thiocompound. Other groups which may also react in this manner include suchas an alkali thiobenzo'ate, alkali loWeralkyl-xanthate, thiourea, alkalithiocyanate, alkali thiosulfate, alkali loweralkylmercaptide, alkalisulfite or an alkali su-lfinate. This may also be carried out on thea-sulfonate compounds to obtain the same product.

The 5,6,7,8-tetrahydro-2-naphthyl-a-mercapto acetic acids may then bereacted with a loweralkyl chlorocarbonate, an alkali isocyanate in thepresence of hydrogen chloride, a loweralkylcarbamyl chloride, adiloweralkylcarbamyl chloride or converted to the metal salt which willreact with a carbamyl chloride to form the correspondingu-mercaptoacetic acid derivatives. The a-meroapto acetic acid may alsobe reacted with succinic anhydride, maleic anhydride or phthalicanhydride to form the corresponding derivative.

The 5,6,7 ,8 tetrahydro 2-naphthyl-a-loweralkylmercapto acetic acid mayfurther be oxidized to the loweralkylsul finyl and loweralkylsulfonylgroups.

In an analogous manner the various a-mercaptoacetates,a-mercaptoacetamides and a-mercaptoacetic acid salts may be preparedfrom the corresponding u-haloacetates, oc-haloacet'amides andot-haloacetic acid salts.

When it is desired to have substitution in other than the 4-position itis convenient to carry out the original Friedel-Crafts reaction on a 1-or 3substituted-5,617,8- tetrahydronaphthlene which will result indirecting the introduction of the glyoxylate side chain to the orthoposition. Conversion may then be carried out as above to obtain thatsubstituent which is desired. Thus, for example, a 1 0r 3-methyl, haloor acylamino compound may be subjected as above to a Friedel-Craftsreaction using t-butyl oxalyl chloride to obtain the corresponding Z-naphthylglyoxylate which in turn may then be reduced to the glycolate.Deacylation of the amino compound may be carried out which in turn maybe diazotized and converted to several groups as above. Conversion ofthe substituted glycolate compounds to the corresponding u-hydroxyderivatives, a-halo, ot-mercapto and a-thiO derivatives may be carriedout as above. The acids, salts, amides and esters may also be formed aspreviously outlined.

Of course it will be understood by one skilled in the art thatvariations in the above procedures can be employed which willprovide-that sequence of reactions which will result in the desiredproduct.

The products of this invention are obtained as racemic mixtures of theirdextro and levorotatory isomers since the a-carbon of the side chain isasymmetric. These may be resolved into the dextro and levorotatoryoptical isomers by conventional methods.

One method of resolution that may be employed is combining the racemiccompound with an optically active compound by salt formation, esterformation, or amide formation to form two diastereomeric products. Ifthe instant acids are added to an optically active base, then twodiastereomeric salts are produced which possess different properties anddifferent solubilities and can be separated by fractionalcrystallization. When the salts have been completely separated byrepeated crystallization, the base is split oil by acid hydrolysis andthe pure d or I acids are obtained. Preferably, the acetic acid isreacted in alcoholic or acetone solution with an equivalent amount ofthe optically active primary, secondary or tertiary amine such ascinchon'idine, cinchonine, quinine, ephedrine, a-methylbenzyl-amine,sec-butylamine, secamylamine, etc. The diastereomeric amine saltsproduced thereby, are separated by fractional crystallization and eachoptically active salt is hydrolyzed with dilute mineral acid to producethe dextro or levo form of that acetic acid. Each optical isomer may bereacted then with XCl or XOX' to produce the corresponding opticallyactive alcoholic derivative. Alternatively, an alkanoate ester may bereacted with an optic-ally active primary or secondary amine such asephedrine, a-methylbenzylamine, sec-butylamine, etc., to produce amixture of diastereomeric acetates which may be separated by fractioncrystallization. Each optically active amide may be hydrolyzed withmineral acid to its respective optically active acid.

Alternatively, an acetate may be reacted with an optically activealcohol such as l-menthol or d-borneol, or l-amethylbenzylalcohol, toproduce a mixture of diastereomeric acetate esters which may beseparated by fractional crystallization. Each optically active ester maybe hydrolyzed with mineral acid or alkali to its respective opticallyactive acid. The optically active acids can also be recovered from thea-methylbenzyl esters by hydrogenolysis in the presence of palladium. Inthis manner the aoxy, halo or thio isomers may be prepared.

We have found that the compounds of this invention exercise a usefuldegree of anti-inflammatory activity in mammals and are eflFective inthe treatment of associated pain and fever and in like conditions whichare responsive to treatment with anti-inflammatory agents. In general,the compounds of this invention are indicated for a wide variety ofmammalian conditions where the symptoms of inflammation and associatedfever and pain are manifested. Exemplary of such conditions are:rheumatic diseases such as rheumatoid arthritis, osteroarthritis andother degenerative joint diseases; soft-tissue rheumatism such astendinitis; muscular rheumatism such as sciatica; pain and inflammationassociated with dental surgery and similar human and veterinary diseaseconditions exhibiting the foregoing symptoms requiring the use of ananti-inflammatory, analgesic and/or an antipyretic agent.

For these purposes, the compounds of this invention are normallyadministered orally, topically, parenterally or rectally. Orally, thesemay be administered in tablets, capsules, suspensions or syrups; theoptimum dosage, of course, depending on the particular compound beingused and the type and severity of the condition being treated. In anyspecific case the appropriate dosage selected will further depend onfactors of the patient which may influence response to the drug; forexample, general health, age, weight, etc. Although the optimumquantities of the compounds of this invention to be used in such mannerwill depend on the compound employed and the particular type of diseasecondition treated, oral dose levels of preferred compounds whenadministered to a mammal in dosages of 0.5 to 100 milligrams perkilogram of body weight per day are particularly useful. The preferredrange is 0.5 to 15 mg./kg. Comparative dosages may be used in topical,parenteral or rectal administration.

Dosage forms may be prepared according to any meth od known to the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents; for example, sweetening agents,flavoring agents, coloring agents, preserving agents, etc. Further, theactive compounds or their derivatives may be administered alone or inadmixture with antacids such as sodium bicarbonate, magnesium carbonate,magnesium hydroxide, aluminum hydroxide, magnesium silicate, etc., andnon-toxic pharmaceutically acceptable excipients. Such excipients maybe, for example, inert diluents such as calcium carbonate, lactose,etc., granulating and disintegrating agents; for example, magnesiumstearate, talc, etc., binding agents; for example, starch gelatin, etc.,suspending agents; for

example, methylcellulose, vegetable oil, etc., dispersing agents; forexample, lecithin, etc., thickening agents; for example, beeswax, hardparatfin, etc., emulsifying agents; for example, naturally-occurringgums, etc., and non-irritating excipients; for example, cocoa butter andpolyethylene glycols.

Various tests in animals can be carried out to show the ability of the5,6,7,8-tetrahydro-2-naphthylacetic acids and derivatives of thisinvention to exhibit reactions that can be correlated withanti-inflammatory activity in humans. One such test is the CarrageenanPaw Edema test, which shows the ability of the instant compounds toinhibit edema induced by injection of an inflammatory agent such ascarrageenan into the tissues of the paw of a rat against non-inflammedcontrols. This carrageenan testing method is known to correlate wellwith anti-inflammatory activity in humans and is a standard test used todetermine anti inflammatory activity. This correlation can be shown bythe activities of compounds known to be clinically active including suchas aspirin, phenylbutazone, cortisone, hydrocortisone and prednisolone.In view of the results of this test, the5,6,7,8-tetrahydro-Z-naphthylacetic acids and derivatives can beconsidered to be active anti-inflammatory agents.

One method for measuring the pain threshold of the compounds of thisinvention is the Randall-Selitto test. Analygesic activity is shown byantinociceptive testing of the inflammed foot of rats and a measurementof their pain response.

Antipyretic assay is carried out by yeast-induced fever tests ofsubcutaneously injected rats. The measurement of rectal temperature iscarried out to determine the response by the test compounds.

In view of the results of the above tests, the 5,6,7,8-tetrahydro-Z-naphthylacetic acids and derivatives of this invention areconsidered to have valuable analgesic and antipyretic properties.

Other tests which can be correlated to show significant activities arethe phenylquinone writhing test for analgesia, polyarthritis in rats andultra-violet erythema in guinea pigs.

The following are detailed examples which show the preparation of thecompounds of this invention. They are to be construed as illustrationsof said compounds and are not intended to be limitations thereof.

EXAMPLE 1 Ethyl 5,6,7,8-tetrahydro-2-naphthylglyoxylate5,6,7,8-Tetrahydro-2-naphthene (0.33 mole) and 50.5 g. (0.37 mole) ofethyl oxalyl chloride are dissolved in 200 ml. of dry1,1,2,2-tetrachloroethane. Anhydrous aluminum chloride 52 g. (0.39 mole)is added in small portions to the reaction mixture with stirring over 2hours. During the addition, the temperature of the mixture is maintainedbetween 16-18 C. The mixture is stirred for an additional hour andallowed to stand overnight. The solution is then slowly poured into 1500ml. of iced saline solution with stirring. After standing, two layersform. The aqueous layer is extracted with 500 ml. of ether and the etherextract is combined with the organic layer which is dissolved in 1500ml. of ether and separated. The ether solution is washed with 10X ml.portions of a 1:1 mixture of saturated sodium chloride solution and 10%HCl solution, and 5 X 100 ml. portions of water. The ether solution isthen dried over anhydrous magnesium sulfate for 1 hour and filtered. Thesolvents are removed by distillation under reduced pressure and theresidue distilled to obtain ethyl5,6,7,8-tetrahydro-2-naphthylglyoxylate.

When ethyl oxalyl chloride in the above example is replaced with methyloxalyl chloride, propyl oxalyl chloride, i-propyl oxalyl chloride,t-butyl oxalyl chloride, or benzyl oxalyl chloride then the productobtained is the methyl. propyl, i-propyl, t-butyl, or benzyl ester of5,6,7,8-tetra hydro-2-naphthylglyoxylate.

1 1 EXAMPLE 2 Ethyl 4-chloro-5,6,7,8-tetrahydro-2-naphthylglyoxylateEthyl 5 ,6,7,8 tetrahydro Z-naphthylglyoxylate (0.38 mole) and 6.1 g. ofiodine (0.048 mole) are dissolved in 100 ml. of carbon tetrachloride. Tothis solution is added a solution of 40.4 g. (0.57 mole) of chlorinedissolved in 365 ml. of carbon tetrachloride over a period of 2 hours.During the addition, the temperature of the reaction mixture ismaintained at 0 C. The mixture is stirred for 3 hours and allowed tostand with gradual Warming to room temperature over hours. The solventis removed by distillation under reduced pressure. The residue isfractionally distilled to obtain ethyl 4-chloro-5,6,7,8-tetrahydro-2-naphthylglyoxy1ate.

When ethyl 5,6,7,8-tetrahydro-2-naphthylglyoxylate in the above exampleis replaced with the esters of Example 1 then the corresponding productis prepared.

EXAMPLE 3 When bromine is used in place of chlorine in Example 2, thecorresponding products are obtained.

EXAMPLE 4 Ethyl 4-nitro-5,6,7,8-tetrahydro-2-naphthylglyoxylate Ethyl5,6,7,8 tetrahydro Z-naphthylglyoxylate (0.066 mole) is added toice-cold concentrated sulfuric acid (18 ml.) and stirred with coolingfor 5 minutes. Concentrated nitric acid (sp. g. 1.51) (2.5 ml.) is addeddropwise, maintaining the temperature between and by water cooling ifnecessary. After addition of the nitric acid is complete, the mixture isstirred for /2 hour, then poured into water. The mixture is madealkaline with sodium hydroxide, then extracted with ether. The etherextract is washed, dried over sodium sulfate, evaporated and the residueis fractionally distilled to obtain ethyl 4-nitro-5,6,7,8-tetrahydro-2-naphthylglyoxylate.

When ethyl p-cyclohexylphenylglyoxylate in the above example is replacedby the esters of Example 1, then the corresponding product is prepared.

EXAMPLE 5 Ethyl 4-trifluoromethyl-5,6,7,8-tetrahydro-2-naphthylglyoxylate To a solution of 0.01 moles of ethyl 4-bromo-5,6,7,8-tetrahydro-2-naphthylglyoxylate in ml. of dimethylformamide is added0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder. Thereaction is shaken in a sealed tube for 5 hours at 140 C., cooled, andthen filtered and evaporated in vacuo. 200 ml. of water is added to theresidue and extracted with ether. The ether extract is dried, evaporatedto dryness and distilled to obtain ethyl4-trifluoromethyl-5,6,7,8-tetrahydro-2-naphthylglyoxylate.

When ethyl 4 bromo 5,6,7,8-tetrahydro-2-naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 3then the corresponding product is obtained.

EXAMPLE 6 Ethyl 4-amino-5,6,7,8-tetrahydro-2-naphthylglyoxylate Amixture of 0.05 moles of ethyl4-nitro-5,6,7,8-tetrahydro-2-naphthylglyoxylate in 100 ml. methanolcontaining 0.05 mole citric acid and 1.5 g. of 5% palladium-oncarbon isshaken with hydrogen at 3 atm. pressure and 27 C. until 3 moles ofhydrogen are absorbed. The mixture is filtered, washed with methanol andthe filtrate concentrated in vacuo to obtain ethyl 4-amino-5,6,7,8-tetrahydro-Z-naphthylglyoxylate, isolated as the citrate salt.

When ethyl 4 nitro 5,6,7,8-tetrahydro-2-naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 4,then the corresponding products are obtained.

12' EXAMPLE 7 Ethyl 4-methylamino-5,6,7,8-tetrahydro-2-naphthylglyoxylate To a solution of 0.01 moles of ethyl 4-amino-5,6,7,8-tetrahydro-Z-naphthylglyoxylate in 100 ml. of acetone is added 0.1 molesof methyl iodide. The reaction mixture is stirred overnight at roomtemperature, filtered and concentrated. The residue is distilled toobtain ethyl 4-methylamino-5,6,7,8-tetrahydro-2-naphthylglyoxylate.

When ethyl 4 amino 5,6,7,S-tetrahydro-Z-naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 6,then the corresponding products are obtained.

When 0.01 moles of acetyl chloride is used in place of methyl iodide andpyridine in place of acetone, then the product prepared is ethyl 4acetylamino 5,6,7,8-tetrahydro-2-naphthylglyoxylate.

EXAMPLE 8 Ethyl 4-dimethylamino-5,6,7,8-tetrahydro-2- naphthylglyoxylateA solution of 0.005 moles of ethyl4-nitro-5,6,7,8-tetrahydro-Z-naphthylglyoxylate and 1.6 ml. of 37%formaldehyde in 50 ml. of methanol is shaken with hydrogen over 0.5 g.of 5% palladium-on-charcoal at 42 lbs. and 27 C. until five moles ofhydrogen are absorbed. The catalyst is filtered off and the filtrate isevaporated in vacuo. The residue is then distilled to obtain ethyl 4-dimethylamino-5,6,7,8-tetrahydro-2-naphthylglyoxylate.

When ethyl 4 nitro 5,6,7,8-tetrahydro-2-naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 4,then the cor responding products are obtained.

EXAMPLE 9 Ethyl 4-cyano-5,6,7,8-tetrahydro-2-naphthylglyoxylate To 0.1moles of ethyl 4-amino-5,6,7,8-tetrahydro-2- naphthylglyoxylate in 35ml. of 28% hydrochloric acid and 100 ml. of cracked ice to maintain thetemperature at 0 C. is added a solution of 7.1 g. (0.102 moles) ofsodium nitrite in 20 ml. of water. The reaction mixture is thenneutralized with sodium carbonate. This diazonium mixture is added to acuprous cyanide solution (prepared from 31.5 g. of copper sulfate and16.2 g. of sodium cyanide in 75 ml. of water). 250 ml. of toluene isalso added and the mixture is stirred for /2 hour. The reaction is thenallowed to stir an additional 2 hours While warming gradually to 50 C.This is then cooled and the toluene separated, dried over sodium sulfateand evaporated to dryness to obtain ethyl 4-cyano-5,6,7,8-tetrahydro-Z-naphthylglyoxylate.

When ethyl 4-amino-5,6,7,8-tetrahydro-Z-naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 6,then the corresponding products are obtained.

EXAMPLE 10 Ethyl 4-fluoro-5,6,7,8-tetrahydro-2-naphthylglyoxylate To0.15 moles of ethyl 4-amino-5,6,7,8-tetrahydro-2- naphthylglyoxylate isadded at 0 C. 44 ml. of 1.5 moles of concentrated hydrochloric acid. Thereaction mixture is maintained at 0 C. and the diazonium salt isprepared with 23.2 g. (0.32 moles) of 95% sodium nitrite in ml. ofwater. To this mixture is rapidly added a solution of 10.4 g. (0.17moles) of boric acid dissolved in 22 g. (0.66 moles) of 60% hydrofluoricacid. The reaction mixture is then stirred for /2 hour and filtered,Washed with 3 x 25 ml. of water, 2x 25 ml. of methanol and 25 ml. ofether. The residual cake is then treated in vacuo. The treated cake isthen placed in a distilling flask and heated to permit spontaneousdecomposition. After the decomposition, the residue is then fractionallydistilled to obtain ethyl 4-fiuoro-5,6,7,S-tetrahydro-2naphthylglyoxylate.

When ethyl 4-amino-5,6,7,8-tetrahydro-2-naphthylglyoxylate in the aboveexample is replaced by the compounds of Example 6, then thecorresponding products are obtained.

EXAMPLE 11 4-Hydroxy-5,6,7,8-tetrahydro-2-naphthylglyoxylic acid 7 To4.5 g.'of ethyl 4-amino-5,6,7,8-tetrahydro-2-glyoxylate suspension in125 ml. of 80% hydrochloric acid and cooled to C. is added dropwise asolution of 1.2 g. of sodium nitrite in 15 ml. of water. After about 10min., 200 ml. of 50% hydrochloric acid is added portion wise and stirredfor hours. The reaction mixture is then poured onto ice water andextracted with chloroform, dried over sodium sulfate and concentrated invacuo. The residue is crystallized to obatin4-hydroxy-5,6,7,8-tetrahydro-Z-naphthylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

'When ethyl 4-amino-5,6,7,8-tetrahydro-2-naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 6,then the corresponding products are obtained.

EXAMPLE 12 Ethyl 4-methoxy-5,6,7,8-tetrahydro-Z-naphthylglyoxylate To astirred suspension of 0.1 moles of sodium hydride in 25 ml. of drydimethylfonmamide which has been cooled to 0 C. is added dropwise asolution of 0.01 moles of ethyl 4-hydroxy-5,6,7,8-tetrahydro-2naphthylglyoxylate in 10 ml. of dimethylformamide. The reaction mixtureis stirred for 15 minutes and 0.015 moles of methyliodide is then addeddropwise. The mixture is allowed to stir overnight at room temperature.200 ml. of water is added and the resulting mixture is extracted wellwith ether. The ether extract is washed with water, dried over sodiumsulfate, evaporated to dryness and distilled to obtain ethyl 4-methoxy-5,6,7,8-tetrahydro-2-naphthylglyoxylate.

When ethyl 4-hydroxy-5,6,7,8-tetrahydro-2-naphthyglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 11,then the corre sponding products are obtained.

When 0.01 moles of acetyl chloride is used in place of methyliodide inthe above reaction, then the product prepared is ethyl 4acetyloxy-5,6,7,8-tetrahydro-2-naphthylglyoxylate.

EXAMPLE 13 4Bromo-5,6,7,8-tetrahydro-2-naphthglyoxylic acid To 0.044moles of ethyl 4amino-5,6,7,8-tetrahydro-2- naphthylglyoxylatesuspension in 225 ml. of 40% hydrobromic acid and cooled to 0 C. isadded dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. ofwater. To this mixture is added a solution of g. of cuprous bromide in350 ml. of 40% hydrobromic acid portion wise and stirred for 15 hours.The reaction mixture is then poured onto ice water, extracted withchloroform, dried over sodium sulfate and concentrated in vacuo. Theresidue is then crystallized to obtain 4-bromo-5,6,7,8-tetrahydro-2-naphthylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 4-amino--5,6,7,8-tetrahydro-2-naphthylglyoxylate in the aboveexample is replaced by the compounds of Example 6, then thecorresponding products are obtained.

EXAMPLE 14 4-Iodo-5,6,7,8-tetrahydro-2-naphthylglyoxylic acid To .05moles of ethyl 4-amino-5,6,7,8-tetrahydro-2- naphthylglyoxylatedissolved in a mixture of 50 g. of ice water and .06 moles ofconcentrated sulfuric acid at 0 C. is added a solution of 0.05 moles of95% sodium nitrite in 8 ml. of water. Stirring is continued for /2 hourand then 1.5 ml. of concentrated sulfuric acid is added. This solutionis poured into an ice cold solution of .06 moles of potassium iodide in10 ml. of water. To this is added 0.075 g. copper bronze with stirringand the solution is warmed slowly on a water bath to about C. for 2hours. After cooling to room temperature the reaction mixture isextracted thrice with 15 ml. portions of chloroform. This is then washedwith dilute thiosulfate solution, Water, dried over sodium sulfate andevaporated in vacuo. The residue is crystallized to obtain4-iodo-5,6,7,8tetrahydro-Z-naphthylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 4-amino-5,'6,7,8-tetrahydro-Z-naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 6,then the corresponding products are obtained.

EXAMPLE 15 4-Mercapto-5,6,7,8-tetrahydro- 2-naphthylglyoxylic acid To0.068 moles of ethyl 4 amino-5,6,7,S-tetrahydro-Z- naphthylglyoxylate in11.1 ml. of concentrated hydrochloric acid and 20 g. of ice is added 4.1g. of sodium nitrite in 2 ml. of Water. This mixture is stirred for 10min. and then added gradually to an ice cold solution of 10.3 g. ofpotassium ethyl xanthate in 14 ml. of water. The reaction is graduallyheated over 45 minutes to 50 C. and stirred an additional 45 minutes.The mixture is then cooled, extracted with ether which is then washedwith water, dilute sodium hydroxide and water, dried over so diumsulfate and evaporated in vacuO. The residue is dissolved in 35 ml. ofboiling ethanol to which is added gradually 13 g. of potassiumhydroxide. The reaction is refluxed an additional hour and thenevaporated to dryness in menu. The residue is dissolved in water andextracted with ether. The alkaline phase is acidified with 6 N sulfuricacid and extracted with ether. The ether is washed with water, driedover sodium sulfate and evaporated to dryness to obtain4-mercapto-5,6,7,8-tetrahydro- 2-naphthylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 4-amino-5,6,7,8-tetrahydro-2-naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 6,then the corresponding products are prepared.

EXAMPLE l6 Ethyl 4-methylthio-5,6,7,S-tetrahydro- 2-naphthylglyoxylateTo 0.014 moles of ethyl-4-mercapto-5,6,7,S-tetrahydro-Z-naphthylglyoxylate in 40 ml. of water containing 0.65 g. of sodiumhydroxide is added 2 ml. of dimethyl sulfate with stirring. The reactionmixture is gradually warmed to 40 C. and stirred for 2 hours. Themixture is cooled and extracted with ether which is washed with water,dried and evaporated in vacuo. The residue is distilled to obtain ethyl4-methylthio-5,6,7,S-tetrahydroZ-naphthylglyoxylate.

When the above 4-methylthio 5 ,6,7,8 tetrahydro-2- naphthylglyoxylate istreated with 30% H 0 then the resultant product is ethyl4-methylsulfinyl-5,6,7,8-tetrahydro-2-naphthylglyoxylate or ethyl4-methylsulfonyl-5,6,7, 8-tetrahydro-2-naphthylglyoxylate.

When 4-mercapto-5,6,7,S-tetrahydro 2 naphthylglyoxylate in the aboveexample is replaced by the compounds of Example 15, then thecorresponding products are prepared.

15 When an equimolar amount of acetyl chloride is used in place ofdimethyl sulfate in the above reaction, then the product prepared isethyl 4-acetylthio-5,6,7,8-tetrahydro-2-naphthylglyoxylate.

EXAMPLE 17 Ethyl 4-chloro-5,'6 ,7,8-tetrahydro- 2-naphthylglycolate Intoa Paar hydrogenation bottle is added 0.144 mole of ethyl4-chloro-5,6,7,8-tetrahydro-2-naphthylglyoxylate, 2 ml. of 0.1 M-ferroussulfate solution; 220 ml. of isopropanol, and 1.0 g. of 84.1% platinumoxide. The mixture is shaken for 2 hours at room temperature withhydrogen gas until 0.144 mole of hydrogen is absorbed. The catalyst isthen filtered oil" and the solution is evaporated in vacuo and theresidue fractionally distilled to obtain ethyl4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolate.

EXAMPLE 18 Ethyl 4-nitro-5,6,7,8-tetrahydro-Z-naphthylglycolate A sodiumborohydride solution 0.302 mole in 13 ml. of water containing 1 drop ofN sodium hydroxide is added dropwise to a stirred solution of 17.9 g.(0.0587 mole) of ethyl 4-nitro-5,6,7, 8-tetrahydro-Z-naphthylglyoxylate,methanol (50 ml.) and water (5 ml.) cooled in an ice-water mixture. Thesolution is partially neutralized with urea-active acid solution (15 ml.each of acetic acid and urea 0.041 mole). The pH after the addition isnear neutral. The pH then is adjusted to acidic by addition of 18 Nsulfuric acid (2.8 ml.). The gum product is extracted with ether. Theether extract is washed with 2x ml. of saturated sodium bisulfite toremove the traces of initial carbonyl compound and then dried overanhydrous sodium sulfite for 2 hours. The drying agent is removed andthe solvent is then removed to obtain ethyl4-nitro-5,6,7,8-tetrahydro-2-naphthylglycolate.

When ethyl 4-nitro-5,6,7,S-tetrahydro 2 naphthylglyoxylate in the aboveexample is replaced by an equimolar amount of the glyoxylate esters ofExamples 1-l7, then the corresponding glycolate product is prepared.

EXAMPLE 19 4-Chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid To asolution of 0.144 moles of ethyl 4-chl0ro-5,6,7,8-tetrahydro-2-naphthylglycolate dissolved in 220 m1. of isopropanol isadded 38 g. (0.7 mole) of potassium hydroxide. This mixture is thenheated at reflux temperature in a nitrogen atmosphere. The solution isconcentrated in vacuo to a viscous oil, which is then dissolved in 500ml. of water and filtered. The filtrate is acidified with 10% HCl ad theprecipitate is taken up in ether. The ether layer is dried, filtered andthe filtrate concentrated to dryness. Recrystallization of residue frombenzenecyclohexane 1:1 gives 4chloro-5,6,7,S-tetrahydro-Z-naphthylglycol acid.

EXAMPLE 20 4Cyano-5,6,7,S-tetrahydro-Z-naphthylglycolic acid A solutionof 0.01 moles of benzyl 4-cyano-5,6,7,8- tetrahydro-Z-naphthylglycolatedissolved in 100 ml. of acetic acid and containing 0.01 mole of hydrogenchloride is shaken with hydrogen over a 5% Pd carbon catalyst until 0.01moles of hydrogen is absorbed. The catalyst is then filtered and thesolution is evaporated to dryness and crystallized to obtain4-cyano-5,6,7,8tetrahydro-2-naphthylglycolic acid.

EXAMPLE 21 Ethyltat-methyl-4-chloro-5,6,7,8-tetrahydro-Z-naphthylglycolate A solution ofmethylmagnesinm iodide is prepared from 6.7 g. (0.047 mole) ofmethyliodide, 1.24 g. (0.051 g.- atom) of magnesium turnings and 40 ml.of anhydrous ether. This solution is added over a period of 1 hour to a16 solution of 0.05 mole of ethyl 4-chloro-5,6,7,8-tetrahydro-2-naphthylglyoxylate. The addition is carried out with vigorous stirringat 0-5 C. The mixture is then allowed to warm to room temperature over10 hours. The mixture is poured into an ice-cold solution of 0.2M-sulfuric acid. The ether layer is separated, extracted with 1%,

sulfuric acid, dried over magnesium sulfate, filtered and evaporated toobtain ethyl a-methyl-4-chloro-5,6,7,8-tetrahydro-Z-naphthylglycolate.

When ethyl 4 chloro-5,6,7,8-tetrahydro-Z-naphthylglyoxylate in the aboveexample is replaced by the glyoxylates of this invention, then thecorresponding a-methyl products are prepared.

When the Grignard reagent used is ethylmagnesium iodide, propylmagnesiumiodide or butylmagnesium iodide, then the corresponding product isprepared.

EXAMPLE 22 l 4-Chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid To aboiling solution of 29.4 g. (0.10 mole) of cinchonidine in 1 liter ofabsolute ethanol is added a boiling solution of 0.10 mole of dl4-chloro-5,6,7,8-tetrahydro-2- naphthylglycolic acid in 500 ml. ofabsolute ethanol. The solution is stirred briefly then allow to cool toroom temperature overnight. The precipitate is collected and Washed with2x 25 ml. of ethanol and air dried. Recrystallization from isopropanolgives white needle crystals. This material is hydrolyzed with 200 ml. of1.2 N-HCl. The white solid is collected, washed with 3 X 50 ml. waterand dried at 55 C. overnight. Recrystallization from benzenecyclohexane3:2 gives l 4 chloro-5,6,7,8-tetrahydro2- naphthylglycolic acid.

When modifications of the above resolution procedure are followed butall 4-chloro-5,6,7,S-tetrahydro-Z-naphthylglycolic acid is replaced byan equimolar amount of the dl glycolic acids and esters of Examples17-21, then the corresponding l-isomer is prepared.

EXAMPLE 23 d 4-Chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid Thecombined ethanol and isopropanol filtrates from Example 22 areevaporated to dryness. This material is triturated with 1 liter ofboiling acetone. The material which does not go into solution isfiltered oil. The filtrate is evaporated to dryness and hydrolyzed withml. of 1.2 N-HCl. The precipitate is collected, Washed with 3X 25 ml. ofwater, and dried at 55 C. Recrystallization from benzene-cyclohexane 3:2gives d 4-chloro-5,6,7,8- tetrahydro 2-naphthylglycolic acid. I

When modifications of the above resolution procedure is followed but dl4-chloro5,6,7,8-tetrahydro-2-naphthylglycolic acid is replaced by anequimolar amount of the dl glycolic acids and esters of Examples 17-21,then the corresponding d-isomer is prepared.

EXAMPLE 24 4-Chloro-5,6,7,8-tetrahydro-Z-naphthylglycol acid, sodiumsalt A solution of 12.4 g. of sodium bicarbonate in ml. of water isadded dropwise to a stirred solution of 0.164 moles of 4chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid in ml. of methanol.The solvent is removed in vacuo and the residue is dried by repeateddistillations with anhydrous ethanol. The crystalline residue istriturated with ether (100 ml.), collected and washed with ether. Theresidue is dried in a vacuum desiccator to obtain 4-chloro 5,6,7,8tetrahydro-Z-naphthylglycolic acid, sodium salt.

When an equimolar amount of sodium bicarbonate in the above reaction isreplaced by the compounds of Table I below, then the corresponding saltis prepared.

17 TABLE I potassium carbonate magnesium bicarbonate.

sodium hydroxide potassium hydroxide calcium hydroxide When the dl, dand l glycolic acid compounds of this invention are used in the abovereaction, then the corresponding salt is prepared.

EXAMPLE 25 4-Chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid,diethylammonium salt Anhydrous diethylamine (0.11 moles) is addeddropwise to a stirred solution of 4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid (0.10 moles) in 100 ml. of n-hexane at C. Theprecipitated diethylammonium salt is collected on a filter Washed withn-hexane and dried in a vacuum desiccator to obtain 4chloro-5,6,7,8-tetrahydro-2- naphthylglycolic acid, diethylammoniumsalt.

When diethylamine in the above reaction is replaced by an equimolaramount of the compounds of Table I, below, then the correspondingproduct is prepared.

TABLE I dimethylamine u-methylbenzylamine fi-hydroxyethylaminecyclohexylamine piperazine triethylamine piperidine phenethylamine Whenthe dl, d and l glycolic acids of this invention are used in the abovereaction, then the corresponding salt is prepared.

EXAMPLE 26 N-isopropyl-4-chloro-5,6,7,8-tetrahydro-Z-naphthylglycolamide Ethyl 4 chloro 5,6,7,8 tetrahydro 2naphthylglycolate (0.1 mole) is stirred with 20 ml. of isopropylamine atabout 35 C. with stirring overnight and the temperature is then raisedto reflux for 28 hours. The reaction mixture is evaporated in vacuo andthe residue distilled to obtainN-isopropyl-4-chloro-5,6,7,8-tetrahydro-2- naphthylglycolamide.

When isopropylamine in the above reaction is replaced by an equimolaramount of the compound of Table I, be-

low then the corresponding product is prepared.

TABLE I diethylamine isothiazolidine ethylmethylamine piperidinet-butylamine morpholine cyclopropylamine N-methylpiperazineN-methylhomopiperazine 'Ethyla,4-dichloro-5,6,7,8-tetrahydro-Z-naphthylacetate A mixture of 0.747mole of ethyl 4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolate is stirredwith 106.67 g. (0.895 mole) of thionyl'chloride at roomtemperature for24 hours and then heated to reflux for 6 hours. The cold reactionmixture is poured into 1125 ml. of ice-cold water with stirring. Themixture is extracted with 800 ml. of ether. The etheral solution iswashed with 450 ml. of cold saturated sodium hydrocarbonate solutionfollowed by washing twice, each time with 250 ml. of cold water. Theethereal solution is dried over anhydrous 18 sodium sulfate andfiltered. The solvent is removed in vacuo to obtain ethyla,4-dichloro-5,6,7,8-tetrahydro-2- naphthylacetate.

EXAMPLE 28 When the procedure of Example 27 is followed but ethyl4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolate is replaced by the a'l,d and l glycolates of this invention, then the corresponding dl, d and la-chloroacetate products are prepared.

EXAMPLE 29 When the procedure of Example 27 is followed =but ethyl4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolate is replaced by theamides of Example 26, then the corresponding product is obtained.

EXAMPLE 30 a,4-Dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid Amixture of 0.167 moles of the ethyl a,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetate and 160 ml. of glacial acetic acidcontaining 40 ml. of 37% hydrochloric acid is refluxed for 20 hours. Themixture is concentrated under reduced pressure to give a gummy residue.The latter material is dissolved in 300 ml. of n-hexane, washed withice-cold water ml. total), dried over sodium sulfate and filtered. Thehexane is removed to give u,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid.

EXAMPLE 31 When the procedure of Example 30 is followed but ethyla,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetate is replaced by the dl,d and l a-chloro-acetates of this invention, then the corresponding dl,d and l u-chloroacetic acids are prepared.

EXAMPLE 32.

a,4-Dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid, sodium salt Asolution of 12.4 g. of sodium bicarbonate in ml. water is added dropwiseto a stirred solution of 0.164 moles ofa,4-dichloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid in cc. ofmethanol. The solvent is removed in vacuo and the residue is dried byrepeated distillations with anhydrous ethanol. The crystalline residueis triturated with ether (100 cc.), collected on a filter, and washedwith ether. Drying in a vacuum desiccator affordsa,4-dichloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid, sodium salt.

EXAMPLE 33 a,4-Dichloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid,diethylammonium salt Anhydrous diethylamine (0.11 moles) is addeddropwise to a stirred solution ofa,3-dichloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid (0.10 moles) in100 m1. of n-hexane at 0 C. The precipitate is collected on a filter,washed with n-hexane, and dried in a vacuum desiccator to obtainu,4-dichloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid, diethylammoniumsalt.

When diethylamine in the above reaction is replaced by an equimolaramount of the compounds of Table I, below, then the correspondingproduct is prepared.

EXAMPLE 34 N-isopropyl a,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide A mixture of 0.016 mole of ethyl a-4-diChl0IO-5,6,7,8-tetrahydro-Z-naphthylacetate and 5.5 ml. of anhydrous isopropylamine arestirred over Linde 4A molecular sieve for 16 hours at room temperature.The reaction mixture is filtered and excess isopropylamine is removed invacuo. The residue is taken up in ether and washed three times with 15ml. of 10% hydrochloric acid. The ether layer is dried over sodiumsulfate, filtered, and the ether is re- 19 moved. The residue istriturated with n-hexane and the precipitate is collected to obtainN-isopropyl oz,4-diChlOI- 5,6,7,8-tetrahydro-2-naphthylacetamide.

When isopropylamine in the above reaction is replaced by an equimolaramount of the compound of Table I, below, then the corresponding productis prepared.

TABLE I diethylamine isothiazolidine ethylmethylamine piperidinet-butylamine morpholine cyclopropylamine N-methylpiperazineN-methylhomopiperazine When isopropylamine in the above reaction isreplaced by ammonia, methylamine or dimethylamine and the reactioncarried out in a bomb at 150 C., then the product prepared isu,4-dichloro-5,6,7,8-tetrahydro 2 naphthylacetamide,N-methyl-aA-dichloro 5,6,7,8 tetrahydro- 2-naphthylacetamide orN,N-dimethyl-u,6-dichloro-5,6,7, 8-tetrahydro-2-naphthylacetamide.

When the dl, d or I a-chloroacetates of this invention are used in theabove reaction, then the corresponding amide is prepared.

EXAMPLE 35 Ethyl a-bromo-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetateTo 0.0476 moles of ethyl 4-chloro 5,6,7,8 tetrahydro-2-naphthylglycolatethere is added slowly with stirring at 4050 C. 23 g. (0.053 moles) ofphosphorus pentabromide. The mixture is stirred at room temperature for16 hours, then diluted with 70 m1. of petroleum ether, and poured into125 ml. of ice-cold water. The organic phase is separated, washed withsaturated aqueous sodium hydrogen carbonate solution, dried overanhydrous sodium sulfate, filtered and the solvent removed in vacuo toobtain ethyl a-brom0-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetate.

When ethyl 4-chloro-5,6,7,8 tetrahydro-2-naphthylglycolate in the aboveprocedure is replaced by d ethyl 4 chloro 5,6,7,8tetrahydro-2-naphthylglycolate, l ethyl 4-chloro 5,6,7,8tetrahydro-Z-naphthylglycolate or N-isopropyl 4-chloro 5,6,7,8tetrahydro-Z-naphthylglycolamide, then the products prepared are l ethylabromo-4-chloro 5,6,7,8 tetrahydro-2-naphthylglycolate, d ethyl a-bromo4 chloro-5,6,7,8-tetrahydro-2-naph thylglycolate or N-isopropyla-bromo-4-chloro-5,6,7,8- tetrahydro-Z-naphthylglycolamide.

When the above procedure is followed using the various glycolates andglycolamides of this invention, then the corresponding a-bromoacetatesand a-bromoacetamides are prepared.

EXAMPLE 36 When the a-bromoacetates of Example 35 are hydrolyzedaccording to the procedures of Examples 30-31, then the correspondingdl, d and l u-bromo-4-chloro 5,6,7,8-tetrahydro-Z-naphthylacetic acidcompounds and the various a-bromoacetic acids are prepared.

EXAMPLE 37 When the u-bromoacetic acid compounds are reacted accordingto the procedures of Examples 32-33, then the correspondinga-bromoacetic acid salts are prepared.

EXAMPLE 3 8 Ethyl a-fluoro-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetate A mixture of 0.33 moles of ethyl a-bromo-4-chloro-5,6,7,8-tetrahydro-Z-naphthylacetate is vigorously stirred at 130l40 C.with 29 g. (0.5 moles) of potassium fluoride in 100 ml. of ethyleneglycol for 12 hours. The reaction mixture is cooled and 400 ml. of wateris added and the crude product separates. The aqueous glycol mixture isextracted With ether, the other is then dried, evapo- 20 rated todryness and upon distillation results in ethyla-fiuoro-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetate.

When ethyl a-bromo 4 chloro 5,6,7,8 tetrahydro- Z-naphthylacetate in theabove procedure is replaced by d ethyl u-bromo 4 chloro5,6,7,8-tetrahydro-2-naphthylacetate, l ethyl a-bromo 4chloro-5,6,7,8-tetrahydro-Z-naphthylacetate or N-isopropyla-bromo-4-chloro- 5,6,7,8 tetrahydro 2 naphthylacetamide, then theproducts prepared are l ethyla-fluoro-4-chloro-5,6,7,S-tetrahydro-2-naphthylacetate, d ethyla-fiuoro-4-chloro-5,6,7,8- tetrahydro-Z-naphthylacetate or N-isopropyla-fluoro-4- chloro-5,6,7,S-tetrahydrO-Z-naphthylacetamide.

When the above procedure is followed using the various a-bromoacetatesand a-bromoacetamides of this invention, then the correspondinga-fluoroacetates and a-fluoroacetamides are prepared.

EXAMPLE 39 When the a-fiuoroacetates of Example 38 are hydrolyzedaccording to the procedures of Examples 303l, then the correspondingu-fiuoro-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetic acid compound andthe various a-fluoroacetic acids are prepared.

EXAMPLE 40 When the u-fiuoroacetic acid compounds are reacted accordingto the procedures of Examples 3233, then the correspondinga-fluoroacetic acid salts are prepared.

EXAMPLE 41 Ethyl wi'0d0-4-ChlO1O-5 ,6,7 ,S-tetrahydro-Z-naphthlyacetateA mixture of 0.1 moles of ethyl a-bromo-4-chloro-5,6,7,S-tetrahydro-Z-naphthlyacetate and 150 g. of sodium iodide in 1 liter ofanhydrous acetone is refluxed for 4 hours. The reaction mixture is thenevaporated to dryness and extracted with ether. The ether is then washedwith water, dried and evaporated to dryness to obtain ethyl a-i0d0-4-chloro-5,6,7,8-tetrahydro-Z-naphthylacetate.

When the above procedure is followed using the various a-bromoacetatesand a-bromoacetamides of this invention then the correspondinga-iodoacetates and a-iodoacet amides are prepared.

' EXAMPLE 42 When the a-iodoacetates of Example 41 are hydrolyzedaccording to the procedures of Examples 30-31, then the correspondinga-iodo-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid compound andthe various a-iodoacetic acids are prepared.

EXAMPLE 43 When the u-iodoacetic acid compounds are reacted according tothe procedures of Examples 32-33, then the corresponding ot-iodoaceticacid salts are prepared.

EXAMPLE 44 a-Mercapto-4-chloro-5,6,7, 8-tetrahydro-2- naphthylaceticacid A mixture of .05 moles of u,4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid and 5 g. of sodium hydrosulfide in ml. of absoluteethanol and under a nitrogen atmosphere is stirred for 15 hours. Themixture is then acidified with 6 N hydrochloric acid. The solvent isremoved in vacuo and the residue is extracted into ether, washed withwater, saturated sodium chloride solution, dried and evaporated todryness to obtain a-mercapto-4-chloro5,6,7,8-tetrahydro-2-naphthylacetic acid.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding u-mercaptoacetatesand wmercaptoacetamides are prepared.

21 EXAMPLE 45 u-Methylthio-4-chloro'5,'6,7,8-tetrahydro-2-naphthylacetic acid Methyl mercaptan is bubbled into a solution of 18.4g. of potassium t-butoxide in 100 ml. of t-butanol for hours and under anitrogen atmosphere. To this is added 0.041 moles ofa,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid in 60 ml. of drytetrahydrofuran. The mixture is then refluxed for 3 hours and allowed tostir at room temperature for hours, acidified with 30 ml. of 6 Nhydrochloric acid. The solvent is removed in vacuo and the residueextracted into ether, washed with water, saturated sodium chloridesolution, dried and evaporated to dryness to obtaina-methylthio-4-chloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding ot-methylthioacetatesand wmethylthioacetamides are prepared.

EXAMPLES 46 a-Ac'etylthio-4-chloro,5,6,7,8-tetrahydro-2- naphthylaceticacid To a solution of 600 ml. of anhydrous ethanol and 21 g. (0.317moles) of potassium hydroxide is added 45 ml. of thioacetic aciddropwise. To this mixture is then added 0.244 moles ofa,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid and stirring iscontinued for 15 hours. The solid which forms is filtered OE and washedwith ethanol. The filtrate is evaporated to dryness and the residue isdissolved in 500 m1. of ether and washed several times with water.Drying the ether and evaporation to dryness results ina-acetylthio-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid.

In a similar manner, the a-propionylthio-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid compounds are prepared.

When the a-chloracetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding ot-acetylthioacetaesand a-acetylthioacetamides are prepared.

EXAMPLE 47 a-Benzoylthio-4-chloro-5,6,7,S-tetrahydro-Z- naphthylaceticacid T o 17.5 ml. of 2 N alcoholic potassium hydroxide solution (0.035mole) is added 4.84 g. (0.035 mole) of thiobenzoic acid. The solution iscooled to room temperature and to this is added in small portions 0.035mole of a,4-dichloro-S,6,7,8-tetrahydro-2-naphthylacetic acid. Thereaction mixture is stirred at room temperature for 25 hours,

then the solvent is removed, the residue dissolved in ether,

filtered and washed with cold water. The ethereal solution is then driedover magnesium sulfate and evaporated to dryness to obtaina-acetylthio-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid.

When the wchloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding a-benzoylthioacetatesand a-benzoylthioacetamides are prepared.

EXAMPLE 48 Ethyl a-thioacetylthio-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetate A mixture of 0.2 moles of sodiumdithioacetate and 0.12 moles of ethyl a,4-dichloro-5,6,7,S-tetrahydro-Z-naphthylacetate in 300 ml. of absolute ethanol is stirred at roomtemperature for 15 hours. The reaction mixture is filtered, washed withabsolute ethanol and evaporated to dryness in vacuo. The residue istreated with ether, filtered and evaporated to dryness to obtain ethyla-thiO- acetylthio 4-chloro-5,6,7,8-tetrahydro-Z-naphthylacetate.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the correspondingu-thioacetylthioacetates and a-thiocetylthioacetamides are prepared.

When sodium dithioformate is used in the above procedure in place ofsodium dithioacetate then the product prepared is ethyla-thioformylthio-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetate.

EXAMPLE 49 a-Thiocyanato-4-ch1oro-5,6,7,S-tetrahydro- Z-naphthylaceticacid To a solution of 300 m1. of anhydrous ethanol and 0.15 moles ofsodium thiocyanate is added 0.12 moles ofa,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid and stirred for 15hours. The reaction mixture is filtered and washed with absoluteethanol. The filtrate is evaporated to dryness, the residue is dissolvedin 250 ml. of ether and washed several times with water. The ether isthen dried and evaporated to dryness to obtaina-thiocyanato-4-chloro-S,6,7,8-tetrahydro-Z-naphthylacetic acid.

When the a-chloroacetate and u-chloroacetamides of this invention areused in the above reaction, then the corresponding u-thiocyanatoacetatesand u-thiocyanatoacetarnides are prepared.

EXAMPLE 50 a-Sulfo-4-chloro-5,6,7,8-tetrahydro-naphthylacetic acid,disodium salt To a solution of 250 ml. of anhydrous ethanol and 0.12moles of sodium sulfite is added 0.1 moles of (1,4'diChl0'ro-5,6,7,8-tetrahydro-Z-naphthylacetic acid, sodium salt. The reactionmixture is stirred for 15 hours, filtered and the residue worked withethanol. The filtrate is evaporated to dryness to obtaina-sulfo-4-chloro-5,6,7,8-tetrahydro- 2-naphthylacetic acid, disodiumsalt.

When sodium sulfinate is used in the above procedure in place of sodiumsulfite, then the product obtained isasulfino-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid, disodiumsalt.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reactions, then the corresponding oc-SlllfO anda-sulfinoacetates and amides are prepared.

EXAMPLE 51 Ethyla-thiosnlfo-4-chloro-5,6,7,8-tetrahydro-Z-naphthylacetate, sodium salt Amixture of .023 moles of ethyl a,4-diChlOIO-5,6,7,8-tetrahydro-2-naphthylacetate and 5.7 g. of sodium thiosulfatepentahydrate in 75 ml. of 40:45 water-alcohol mixture is refluxed for 2hours. An additional 0.8 g. of sodium thiosulfate pentahydrate is thenadded and refluxing continued another /2 hour. The reaction mixture isthen evaporated to dryness in vacuo, azeotroped with ethanol andevaporated to dryness in vacuo again. The residue is triturated withether, filtered and evaporated to dryness. The residue is thentriturated with hexane and the resultant gum is dissolved in alcohol andevaporated to dryness in vacuo to obtain ethyl octhiOSlllfO-4-Ch10l'0-5,6,7,8-tetrahydro-2-naphthylacetate, sodium salt.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding a-thiosulfoacetateand a-thiosulfoacetamides are prepared.

EXAMPLE 52 a-Amidinothio-4-chloro-5,6,7,8-tetrahydro- 2-naphthylaceticacid, hydrochloride Tiourea 15.2 g. (0.2 moles) is dissolved in ml. ofabsolute ethanol and to this is added 0.11 moles of ,4-dichloro-S,6,7,8-tetrahydro 2 naphthylacetic acid. The mixture isstirred for 15 hours at 0 C. The mixture is then filtered to obtaina-amidinothio-4-chloro-5,6,7,8-tetrahydrO-Z-naphthylacetic acid,hydrochloride.

When the a-chloroacetates and acetamides of this invention are used inthe above procedures then the corresponding a-amidinoacetates andacetamides are prepared.

EXAMPLE 3 a-Ethoxythiocarbamy1thio-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid Ethylxanthic acid, potassium salt, 3.63g. (0.22 moles) is dissolved in 150 ml. of absolute ethanol withstirring. To this solution is added 0.11 moles of a,4-dichloro-5,6,7,8-tetrahydro 2 naphthylacetic acid and the mixture stirred for hours.The solid which separates is collected and washed with absolute ethanol.The solid is then treated with acetone and the insoluble materialfiltered ofi. The filtrate is concentrated to dryness to obtaina-ethoxythiocarbamylthio 4-ch1oro-5,6,7,8-tetrahydro-2-naphthlaceticacid.

When the a-chloroacetates and acetamides of this invention are used inthe above procedure then the corresponding a-ethylxanthylacetates andacetamides are prepared.

EXAMPLE 54 a-Ethoxycarbonylthio-4-chloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid A solution ofa-mercapto-4-chloro-5,6,7,8-2-naphthy1- acetic acid (0.02 moles) in 25ml. of pyridine is cooled in an ice bath. To this is added dropwise 2.1mol (0.022 moles) of ethyl chloroformate. The mixture is then stirredfor 2 hours, diluted with ether and filtered. The mixture is basifiedwith 10% sodium bicarbonate solution. The alkaline mixture is workedwith ether, then acidified with 10% hydrochloric acid, washed withether, dried and filtered. The solvent is removed and the residue istriturated with hexane to obtain a-ethoxycarbonylthio-4-chloro-5,6,7,S-tetrahydro-2-naphthylacetic acid.

When the a-mercaptoacetates and acetamides of this invention are used inthe above procedure then the corresponding a-ethoxycarbonylthioacetatesand acetamides are prepared.

EXAMPLE 55 a-Diethylcarbamylthio-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid A solution ofa-mercapto-4-chloro-5,6,7,8-2-naphthylacetic acid (0.2 moles) in 25 ml.of pyridine is cooled in an ice bath. To this is added dropwise 0.022moles of diethylcarbamylchloride. The mixture is then stirred for 2hours, diluted with ether and filtered. The mixture is then basifiedwith 10% sodium bicarbonate solution. The alkaline mixture is washedwith ether, acidified with 10% hydrochloric acid, extracted with etherwhich in turn is washed with cold water, dried and evaporated todryness. Trituration with hexane results inu-diethylcarbamylthio-4-chlor0-5,6,7,8-tetrahydro-2-naphthylacetic acid.

When the procedure of Example 55 is followed but diethylcarbonate isreplaced by succinic anhydride, maleic anhydride or phthalic anhydride,then the products .prepared are on butyrylthio 4 chloro 5,6,7,8tetrahydro- 2-naphthylacetic acid, u-butenolylthio- 4F chloro-5,6,7, 8tetrahydro-2-naphthylacetic acid andu-(a-carboxybenzoylthio)-4-chloro-5,6,7,8-tetrahydro-2-naphthylaceticacid.

When the various a-mercaptoacetates and acetamides of this invention areused in the above procedure, then the corresponding product is prepared.

EXAMPLE 57 When a methylthio 4 chloro 5,6,7,8 tetrahydro-2-naphthylacetic acid is treated with 30%hydrogen peroxide, then theresultant product is 'a-methylsulfinyl-4- chloro 5,6,7 ,8 tetrahydro 2naphthylacetic acid or amethylsulfonyl-4-chloro-5,6,7,8-tetrahydro 2naphthylacetic acid. I

I claim:

1. The compound u,4 dichloro 5,6,7,8-tetrahydro-2- naphthylacetic acid.

2. The compound 41,4 dichloro 5,6,7,8-tetrahydro-2- naphthylacetic acid,diethylammonium salt.

References Cited Oka: Chemical Abstracts, vol. 55, col. 24656d-e JOSEPHE. EVANS, Primary Examiner M. W. GLYNN, Assistant Examiner U.S. Cl. X.R.

260247.l, 247.2 A, 268 C, 293.62, 455 C, 456R, 465 F, 469, 470, 471 R,472, 473 F, 488 CD, 501.21, 5005 H, 501.11, 501.12, 516, 518 A, 519, 558R, 558 H, 558 A, 559 R, 559 H, 559 A, 515 A, 599, 268 R,v 448 ,R;424-448, 250, 267, 304, 308, 309, 315, 316, 324, 333, 3 319

